On the current trend toward the aging society, abnormal acceleration of bone resorption in a human advanced in years involves many of various senile diseases. In particular, senile osteoporosis is prominent and about to become a great social problem. When the present pharmacotherapy for this senile osteoporosis is viewed, it is conducted to administer (1) estrogen, (2) protein anabolic hormones, (3) calcitonin, (4) vitamin D or (5) bisphosphonates. However, their effects are found only in improvement of subjective symptom, and hence there is no critical therapy under the circumstances.
On the other hand, it is considered that factors causing osteoporosis include two of calcification and decalcification, and abnormal decomposition of supporting tissue, collagen. However, the development of pharmaceutical agents by paying attention to the abnormal acceleration of collagen decomposition is only now under way. It is reported that a group of cathepsins takes part in this collagen decomposition to the greatest extent, and cathepsin L among the group of cathepsins, which belongs to cysteine proteases, particularly deeply involves the collagen decomposition [FEBS Letters, 269, pp. 189-193 (1990); and FEBS Letters, 280, pp. 311-315 (1991)]. It has recently be found that cathepsin K, which is a family enzyme of cathepsin L, also takes parts in bone resorption [J. Biol. Chem., 271, pp. 12517-12524 (1996)]. With respect to compounds which inhibit cysteine proteases, epoxysuccinic acid derivatives similar to those of the present application have been reported in, for example, Japanese Patent Application Laid-Open No. 104683/1996 and European Patent Publication No. 655447A1. However, these compounds inhibit both enzymes of cathepsin L and cathepsin B without any selectivity. It has been reported that cathepsin B does not take part in bone resorption [FEBS Letters, 321, pp. 247-250 (1993)], and is an enzyme related to an immune system such as antigen presenting [FEBS Letters, 324, pp. 325-330 (1993)]. It is hence apprehended that immunodeficiency may be caused if cathepsin B is inhibited. In order to inhibit bone resorption selectively, it is therefore necessary to use an inhibitor which selectively inhibits cathepsin L and family enzymes thereof. However, such a selective inhibitor has not been found yet.
It is an object of the present invention to provide a novel compound which inhibits cathepsin L and its family enzymes at a concentration lower than against other cysteine proteases, and in other words, a novel compound useful as an agent for treating and preventing metabolic osteopathy such as osteoporosis, hypercalcemia, Paget's disease, hyperparathyroidism and bone metastasis of cancer.